Journal Article

XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis

Kam, Shing, Elinav, Eran, Likhter, Mariya, Ben-Ari, Ziv, Malissen, Bernard, Cohen, Merav, Shlomi-Loubaton, Shir, Hermon, Hila, Gur, Chamutal, Barboy, Oren, Amit, Ido, Safran, Michal, Pfister, Dominik, Roth, Susanne, Jaitin, Diego Adhemar, Weiner, Assaf, David, Eyal, Li, Baoguo, Cohen-Ezra, Oranit, Ramadori, Pierluigi, Ben Yakov, Gil, Heikenwälder, Mathias, Davidov, Yana, Henri, Sandrine, Giladi, Amir, Yofe, Ido, Qiu, Mengjie, Weber, Achim, Deczkowska, Aleksandra, Suhail, Yousuf, Lahat, Eylon, Goitein, David

2021

Overview

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1 DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1 + cDC1 as an important driver of liver pathology. Single-cell analyses reveal cDC1 as conserved immunological drivers of non-alcoholic steatohepatitis in mice and humans

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2504/133 / 631/250/256/2515 / 692/163/2743/2037 / Animal models / Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / Blocking antibodies / Bone marrow / Bone Marrow Cells - immunology / Bone Marrow Cells - pathology / Cancer Research / Cellular Reprogramming - genetics / Cellular Reprogramming - immunology / Cirrhosis / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - pathology / Depletion / Diet, High-Fat - adverse effects / Disease Models, Animal / Fatty liver / Fatty Liver - genetics / Fatty Liver - immunology / Fatty Liver - pathology / Female / Hemopoiesis / Hepatocytes / Humans / Immunology / Infectious Diseases / Inflammation / Life Sciences / Liver / Liver - immunology / Liver - pathology / Liver cancer / Liver cirrhosis / Liver diseases / Liver failure / Lymph nodes / Lymph Nodes - immunology / Lymph Nodes - pathology / Lymphocytes / Lymphocytes T / Male / Metabolic Diseases / Mice / Molecular Medicine / Molecular modelling / Neurosciences / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - immunology / Non-alcoholic Fatty Liver Disease - pathology / Osteoprogenitor cells / Pathology / Receptors, Chemokine - genetics / Receptors, Chemokine - immunology / T-Lymphocytes - immunology / T-Lymphocytes - pathology